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Multicenter Study
. 2024 Oct:108:105352.
doi: 10.1016/j.ebiom.2024.105352. Epub 2024 Sep 19.

Post-surgery sequelae unrelated to disease progression and chemotherapy revealed in follow-up of patients with stage III colon cancer

Alexia Mirandola  1 , Andrei Kudriavtsev  1 , Catalina Isabel Cofre Muñoz  2 , Raquel Comas Navarro  3 , Marco Macagno  4 , Saidi Daoud  1 , Cynthia Sanchez  1 , Brice Pastor  1 , Ekaterina Pisareva  1 , Mireia Sanchis Marin  3 , Javier Gonzalo Ruiz  3 , Alejandro Piris  3 , Ariadna Garcia Rodriguez  3 , Nadia Saoudi Gonzalez  3 , Ana Vivancos  3 , Virginia Quarà  4 , Alfredo Mellano  4 , Felice Borghi  4 , Giorgio Corti  4 , Caterina Marchiò  5 , Anna Sapino  5 , Alice Bartolini  4 , Giovanni Crisafulli  6 , Alberto Bardelli  6 , Massimo Di Maio  7 , Gerald Lossaint  8 , Florence Frayssinoux  1 , Evelyne Crapez  9 , Marc Ychou  9 , Ramon Salazar Soler  2 , Elisabetta Fenocchio  4 , Paula X Fernandez Calotti  2 , Thibault Mazard  9 , Cristina Santos Vivas  10 , Elena Elez  3 , Federica Di Nicolantonio  11 , Alain R Thierry  12
Affiliations
Multicenter Study

Post-surgery sequelae unrelated to disease progression and chemotherapy revealed in follow-up of patients with stage III colon cancer

Alexia Mirandola et al. EBioMedicine. 2024 Oct.

Abstract

Background: We studied the poorly-known dynamics of circulating DNA (cir-nDNA), as monitored prospectively over an extended post-surgery period, in patients with cancer.

Methods: On patients with stage III colon cancer (N = 120), using personalised molecular tags we carried out the prospective, multicenter, blinded cohort study of the post-surgery serial analysis of cir-nDNA concentration. 74 patients were included and 357 plasma samples tested.

Findings: During post-operative follow-up, the patients' median cir-nDNA concentration was greater (P < 0.0001 in the [43-364 days range]) than both the median value in healthy individuals and the pre-surgery value. These cir-nDNA levels were highly associated with NETs markers (P-value associating MPO and cir-nDNA, and NE and cir-nDNA are 6.6 x 10-17, and 1.9 x 10-7), in accordance with previous reports which indicate that cir-nDNA are NETs by-products. Unexpectedly, in 34 out of 50 patients we found that NETs continued to be formed for an extended duration post-surgery, even in patients without disease progression. Given that this phenomenon was observed in patients without adjuvant CT, and in patients >18 months post-surgery, the data suggest that the persistence of NETs formation is not due to the adjuvant CT.

Interpretation: (1), Given the inter-patient heterogeneity, the post-surgery cir-nDNA level cannot be considered a reliable value, and caution must be exercised when determining mutation allele frequency or the mutation status; and (2), specific studies must be undertaken to investigate the possible clinical impact of the persistent, low-grade inflammation resulting from elevated NETs levels, such as observed in these post-surgery patients, given that such levels are known to potentially induce adverse cardiovascular or thrombotic events.

Funding: This work was supported by the H2020 European ERA-NET grant on Translational Cancer Research (TRANSCAN-2).

Keywords: Biomarkers; Circulating DNA; Colorectal cancer; Diagnostic; Neutrophil extracellular traps; Post-surgery; Tumour biology.

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Conflict of interest statement

Declaration of interests TM has received personal fees from AMGEN, PIERRE FABRE, MSD, GALAPAGOS, SERVIER, MERCK SERONO and SANOFI, and TM declare participation on DSMB of the ongoing study PRODIGE 70 from FFCD, outside the submitted work. CICM has received personal fees from Instituto de Salud Carlos III/ISCIII and the Asociación Española Contra el Cancer/AECC, outside the submitted work. PXFC and CSV had received personal fees from Merck, Merck KGaA and Amgen, outside the submitted work. RSS is an advisor for GSK, Sanofi Genzyme and an expert testimonyEsteve, Laboratorios Servier, also has received personal fees from SACE Medhealth and WNT Pharma, outside the submitted work. AbB has received personal fees from Neophore, AstraZeneca Guardant Health, Kither Biotech and he is an advisor for Neophore, Roche/Genentech Global CRC, outside the submitted work. FdN has received personal fees from Illumina and Pierre Fabre, outside the submitted work. EF has received personal fees from Amgen and Pierre Fabre and Merck, outside the submitted work. MDM reports grants from GlaxoSmithKline, Exelixis, Roche, BeiGene, Novartis, Merck Sharp & Dohme, Pfizer; and he has received personal fees from Amgen, Merck, Ipsen, Viatris, Janssen, Astellas, AstraZeneca, Boehringer Ingelheim, Roche, Novartis, Servier, outside the submitted work. CM has received personal fees from Menarini, Roche, Veracyte, Illumina, Bayer and Daiichi Sakyo, outside the submitted work. AV reports grants from AVINCYTE, ROCHE and is an advisor for INCYTE, ROCHE, and BAYER, outside the submitted work. EE has received personal fees from Amgen, Bayer, Cure Teq, AG Hoffmann-La Roche, BMS, Boehringer Ingelheim, Janssen, Lilly, Medscape, Merck Serono, MSD, Novartis, Organon, Pfizer, Pierre Fabre, Repare Therapeutics Inc., RIN Institute Inc., Sanofi, Seagen, Servier and Takeda, outside the submitted work. NSG has received personal fees from AMGEN, MERCK, outside the submitted work, outside the submitted work. ART reports grants from SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553 and Société Française des Acides Nucléiques Circulants (SFAC), outside the submitted work. This does not alter our adherence to journal policies on sharing data and materials. All authors critically reviewed and approved the manuscript.

Figures

Fig. 1
Fig. 1
Flow chart of the clinical study (a) and description of the patient cohort (b, c). Patient cohort: a: Study cohort flow chart. b: Distribution of the clinical study patients (N = 74) with respect to post-operative follow-up. The number and proportion (%) of patients are grouped according to the follow-up periods in which serial analysis ended: 1–6 (between 1 and 6 months); 6–12 (up to 6 and 12 months range); 12–18 (up to 12 and 18 months range); 18–24 (up to 18 and 24 months range); and >24 months. c: Distribution presented as numbers of patients; d: Distribution presented as proportions, %. (c) Frequency of relapse and adverse events in the study cohort (%). The post-surgery time period follow up is heterogenous due to the late date of inclusion (32–804 days, range) and the end of the clinical study (Fig. 1 and Table 1): >2 months (N = 64), >6 months (N = 50), >12 months (N = 29), >18 months (N = 15), >24 months (N = 9) Note, given that NETs formation is particularly associated with the inflammatory process and thrombosis, this study groups patients experiencing ITE, and excludes patients experiencing neurotoxicity or other adverse events.
Fig. 2
Fig. 2
Pre- and post-surgery cir-nDNA values in stage III colon patients with cancer (a). Values are arbitrarily categorised according to pre-surgery period or these follow-up periods: 15–42 days; from 42 days up to one year; between one and two years; more than 2 years. The dotted line corresponds to the median value obtained in healthy individuals. Proportion of cir-nDNA values being higher than the healthy individual median value (b) or higher than the pre-surgery value (c). ∗Mann–Whitney test.
Fig. 3
Fig. 3
Evolution of all the values of cir-nDNA, MPO and NE markers determined in the cohort study patients upon follow-up period ranges. Comparison of cir-nDNA, MPO and NE values with healthy median values or pre-surgery values. Healthy subjects' median values vs pre-surgery (a); vs 15–42 days post-surgery (b); vs follow-up between 43 days and one year (c); vs follow-up between one to two years (d); and vs follow-up of more than 2 years (e); pre-surgery vs 15–42 days post-surgery (f); vs follow-up between 43 days and one year (g); vs follow-up between one and two years (h); and vs follow-up of more than 2 years (i). Data are expressed as the ratio of the post-surgery value over healthy individual median value, or over the pre-surgery value; samples with value over HI median or pre-surgery value are over 100%. Spearman correlation study between all MPO, NE and cir-nDNA values. (j), pre-surgery values; Spearman P-value associating MPO and NE, MPO and cir-DNA and NE and cir-nDNA are 1.6 x 10−5, 1.0 x 10−3 and 2.3 x 10−2; (k), post-surgery values. Spearman P-value associating MPO and NE, MPO and cir-DNA and NE and cir-nDNA are 1.7 x 10−21, 1.5 x 10−14 and 2.1 x 10−7; and (l), pre- and post-surgery values. Spearman P-value associating MPO and NE, MPO and cir-DNA and NE and cir-nDNA are 1.5 x 10−22, 6.6 x 10−17, and 1.9 x 10−7. Regression curves of the association between all MPO, NE and cir-nDNA values. MPO vs NE, MPO vs cir-nDNA, and cir-nDNA vs NE. R values are (j) 0.44, 0.11, 6.1 x 10−3; (k) 0.36, 0.27 and 0.05; (l) 0.35, 0.23 and 0.03, respectively.
Fig. 4
Fig. 4
Illustrative examples of clinical cases. Patients with two types of marker dynamics during follow-up of patients experiencing no relapse or ITE, and showing MPO, NE, and cir-nDNA at a persistently elevated level (a, b, and c), or returning to control levels (d, e, and f). Orange arrows: start of Adjuvant CT; Brown arrows: end of Adjuvant CT.
Fig. 5
Fig. 5
Illustrative examples of clinical cases. Monitoring of patients experiencing relapse (a, b, c and d) or ITE (e, f, g and h). Orange arrows: start of Adjuvant CT; Brown arrows: end of Adjuvant CT; Cyan arrows: relapse or ITE; Grey arrows: end of ITE.
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